Editing Hemoglobin (section)

===Allosteric===
{{Further|Oxygen-hemoglobin dissociation curve}}
Carbon ''di''oxide occupies a different binding site on the hemoglobin. At tissues, where carbon dioxide concentration is higher, carbon dioxide binds to allosteric site of hemoglobin, facilitating unloading of oxygen from hemoglobin and ultimately its removal from the body after the oxygen has been released to tissues undergoing metabolism. This increased affinity for carbon dioxide by the venous blood is known as the [[Bohr effect]]. Through the enzyme [[carbonic anhydrase]], carbon dioxide reacts with water to give [[carbonic acid]], which decomposes into [[bicarbonate]] and [[proton]]s:

:CO<sub>2</sub> + H<sub>2</sub>O → H<sub>2</sub>CO<sub>3</sub> → HCO<sub>3</sub><sup>−</sup> + H<sup>+</sup>

[[File:Hemoglobin saturation curve.svg|left|thumb|The sigmoidal shape of hemoglobin's oxygen-dissociation curve results from cooperative binding of [[oxygen]] to hemoglobin.]]
Hence, blood with high carbon dioxide levels is also lower in [[pH]] (more [[acid]]ic). Hemoglobin can bind protons and carbon dioxide, which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places on the protein, while carbon dioxide binds at the α-amino group.<ref>Nelson, D. L.; Cox, M. M. (2000). ''Lehninger Principles of Biochemistry'', 3rd ed. New York: Worth Publishers. p. 217, {{ISBN|1572599316}}.</ref> Carbon dioxide binds to hemoglobin and forms [[carbaminohemoglobin]].<ref>{{cite book |edition=11 |publisher=Elsevier Saunders |isbn=978-0-7216-0240-0 |page=511 |last=Guyton |first=Arthur C. |author2=John E. Hall |title=Textbook of Medical Physiology |location=Philadelphia |year=2006}}</ref> This decrease in hemoglobin's affinity for oxygen by the binding of carbon dioxide and acid is known as the [[Bohr effect]]. The Bohr effect favors the T state rather than the R state. (shifts the O<sub>2</sub>-saturation curve to the ''right''). Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon dioxide and protons are released from hemoglobin, increasing the oxygen affinity of the protein. A reduction in the total binding capacity of hemoglobin to oxygen (i.e. shifting the curve down, not just to the right) due to reduced pH is called the [[root effect]]. This is seen in bony fish.

It is necessary for hemoglobin to release the oxygen that it binds; if not, there is no point in binding it. The sigmoidal curve of hemoglobin makes it efficient in binding (taking up O<sub>2</sub> in lungs), and efficient in unloading (unloading O<sub>2</sub> in tissues).<ref>{{YouTube|6AfRX6oh9-E|Lecture – 12 Myoglobin and Hemoglobin}}</ref>

In people acclimated to high altitudes, the concentration of [[2,3-Bisphosphoglycerate]] (2,3-BPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower [[oxygen tension]]. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a ''heterotropic'' allosteric effect. Hemoglobin in organisms at high altitudes has also adapted such that it has less of an affinity for 2,3-BPG and so the protein will be shifted more towards its R state. In its R state, hemoglobin will bind oxygen more readily, thus allowing organisms to perform the necessary metabolic processes when oxygen is present at low partial pressures.<ref>{{cite book |title=Biochemistry |edition=Eighth |publisher=W. H. Freeman |year=2015 |location=New York |isbn=978-1-4641-2610-9}}{{page needed|date=December 2021}}</ref>

Animals other than humans use different molecules to bind to hemoglobin and change its O<sub>2</sub> affinity under unfavorable conditions. Fish use both [[adenosine triphosphate|ATP]] and [[guanosine triphosphate|GTP]]. These bind to a phosphate "pocket" on the fish hemoglobin molecule, which stabilizes the tense state and therefore decreases oxygen affinity.<ref name="Rutjes-2007">{{cite journal |last=Rutjes |first=H. A. |author2=Nieveen, M. C. |author3=Weber, R. E. |author4=Witte, F. |author5=Van den Thillart, G. E. E. J. M. |title=Multiple strategies of Lake Victoria cichlids to cope with lifelong hypoxia include hemoglobin switching |journal=AJP: Regulatory, Integrative and Comparative Physiology |date=20 June 2007 |volume=293 |issue=3 |pages=R1376–83 |pmid=17626121 |doi=10.1152/ajpregu.00536.2006}}</ref> GTP reduces hemoglobin oxygen affinity much more than ATP, which is thought to be due to an extra [[hydrogen bond]] formed that further stabilizes the tense state.<ref name="Gronenborn-1984">{{cite journal |last=Gronenborn |first=Angela M. |author2=Clore, G. Marius |author3=Brunori, Maurizio |author4=Giardina, Bruno |author5=Falcioni, Giancarlo |author6=Perutz, Max F. |title=Stereochemistry of ATP and GTP bound to fish haemoglobins |journal=Journal of Molecular Biology |volume=178 |issue=3 |pages=731–42 |year=1984 |pmid=6492161 |doi=10.1016/0022-2836(84)90249-3}}</ref> Under hypoxic conditions, the concentration of both ATP and GTP is reduced in fish red blood cells to increase oxygen affinity.<ref name="Weber-1988">{{cite journal |last=Weber |first=Roy E. |author2=Frank B. Jensen |title=Functional adaptations in hemoglobins from ectothermic vertebrates |journal=Annual Review of Physiology |year=1988 |volume=50 |pages=161–79 |pmid=3288089 |doi=10.1146/annurev.ph.50.030188.001113}}</ref>

A variant hemoglobin, called [[fetal hemoglobin]] (HbF, α<sub>2</sub>γ<sub>2</sub>), is found in the developing [[fetus]], and binds oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the [[placenta]] is able to take oxygen from maternal blood.

Hemoglobin also carries [[nitric oxide]] (NO) in the globin part of the molecule. This improves oxygen delivery in the periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue in globin; the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin influences various NO-related activities such as the control of vascular resistance, blood pressure and respiration. NO is not released in the cytoplasm of red blood cells but transported out of them by an anion exchanger called [[Anion Exchanger 1|AE1]].<ref>{{cite book |last=Rang |first=H.P. |author2=Dale M.M. |author3=Ritter J.M. |author4=Moore P.K. |title=Pharmacology, Fifth Edition |year=2003 |publisher=Elsevier |isbn=978-0-443-07202-4}}{{page needed|date=December 2021}}</ref>